Quinazolinone derivatives as ALDH-2 inhibitors

Abstract

Disclosed are novel quinazolinone derivatives of formula: wherein: R 1 is optionally substituted phenyl or optionally substituted heteroaryl; R 2 is 3-hydroxy, 4-hydroxy, 3-NHR 4 or 4-NHR 4 , in which R 4 is hydrogen, —C(O)R 5 , —C(O)NHR 6 , or —SO 2 R 6 ; in which R 5 is optionally substituted lower alkyl or optionally substituted lower alkoxy; and R 6 is optionally substituted lower alkyl; R 3 is hydrogen, lower alkyl, lower alkoxy, or halo; V is oxygen, sulfur, or —NH—; and W is lower alkylene of 1-3 carbon atoms, which are useful as ALDH-2 inhibitors for treating mammals for various disease states, such as treatment for cocaine dependency and alcohol dependency.

1. A compound of the Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is phenyl optionally substituted by 1, 2 or 3 groups chosen from carboxyl, carboxyalkyl, carboxamido, cyano, halo, and lower alkyl optionally substituted by halo, or R 1  is oxadiazolyl optionally substituted by a phenyl group that is optionally substituted by 1, 2 or 3 groups chosen from halogen, cyano, alkoxy of 1-6 carbon atoms, alkynyl of 1-6 carbon atoms, or lower alkyl of 1-6 carbon atoms, which is optionally substituted by hydroxy, 2, or 3 halo atoms, cyano, or cycloalkyl of 4-6 carbon atoms; 
 R 2  is 3-hydroxy, 4-hydroxy, 3—NHR 4  or 4—NHR 4 , in which R 4  is hydrogen, —C(O)R 5 , —C(O)NHR 6 , or —SO 2 R 6 ; in which
 R 5  is lower alkyl of 1-6 carbon atoms or lower alkoxy of 1-6 carbon atoms; and 
 R 6  is lower alkyl of 1-6 carbon atoms; 
 
 R 3  is hydrogen, lower alkyl of 1-6 carbon atoms, lower alkoxy of 1-6 carbon atoms, or halo; 
 V is oxygen, sulfur, or —NH—; and 
 W is lower alkylene of 1-3 carbon atoms. 
 
     
     
       2. The compound of  claim 1 , wherein said optionally substituted phenyl is monosubstituted, W is methylene, R 2  is 4-hydroxy, R 3  is hydrogen, and V is oxygen. 
     
     
       3. The compound of  claim 1 , wherein said optionally substituted phenyl is disubstituted, W is methylene, R 2  is 4-hydroxy, R 3  is hydrogen, and V is oxygen. 
     
     
       4. The compound of  claim 2 , selected from
 3-(4-hydroxyphenyl)-7-[(5-phenyl(1,2,4-oxadiazol-3-yl))methoxy]-3-hydroquinazolin-4-one; 
 3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-hydroquinazolin-4-one; 
 7-({5-[2-methoxyphenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-(4-hydroxyphenyl)-3-hydroquinazolin-4-one; and 
 3-(3-{[3-(4-hydroxyphenyl)-4-oxo-3-hydroquinazolin-7-yloxy]methyl}-1,2,4-oxadiazol-5-yl)benzenecarbonitrile. 
 
     
     
       5. The compound of  claim 3 , selected from
 7-({5-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-(4-hydroxyphenyl)-3-hydroquinazolin-4-one; 
 3-(4-hydroxyphenyl)-7-({5-[4-methoxy-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-hydroquinazolin-4-one; 
 7-({5-[2,5-bis(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-(4-hydroxyphenyl)-3-hydroquinazolin-4-one; and 
 7-({5-[3,5-bis(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)-3-(4-hydroxyphenyl)-3-hydroquinazolin-4-one. 
 
     
     
       6. The compound of  claim 1 , wherein R 1  is phenyl optionally substituted by 1, 2 or 3 groups chosen from carboxyl, carboxyalkyl, carboxamido, cyano, halo, or lower alkyl optionally substituted by halo. 
     
     
       7. The compound of  claim 6 , wherein R 1  is monosubstituted phenyl. 
     
     
       8. The compound of  claim 6 , wherein R 1  is disubstituted phenyl. 
     
     
       9. The compound of  claim 8 , wherein each of said two substituents is independently selected from carboxyl, carboxyalkyl, carboxamido, or cyano. 
     
     
       10. The compound of  claim 6 , wherein W is methylene, R 2  is 4-hydroxy and V is oxygen. 
     
     
       11. The compound of  claim 1 , selected from
 3-{[3-(4-hydroxyphenyl)-4-oxo-3-hydroquinazolin-7-yloxy]methyl}benzenecarbonitrile; 
 3-{[3-(4-hydroxyphenyl)-4-oxo-3-hydroquinazolin-7-yloxy]methyl}benzamide; 
 methylethyl 3-{[3-(4-hydroxyphenyl)-4-oxo-3-hydroquinazolin-7-yloxy]methyl}benzoate; and 
 3-{[3-(4-hydroxyphenyl)-4-oxo-3-hydroquinazolin-7-yloxy]methyl}benzoic acid. 
 
     
     
       12. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of Formula I, and at least one pharmaceutically acceptable carrier.